Autoimmune mechanisms in a novel Aire-deficient model of peripheral neuropathy

DESCRIPTION (provided by applicant): Chronic Inflammatory Demyelinating Polyneuropathy (CIDP) is the most common acquired chronic autoimmune neuropathy and is characterized by demyelination and immune cell infiltration of the peripheral nervous system (PNS). CIDP is associated with progressive Weaknesses, paresthesias, and sensory dysfunction and is the chronic counterpart of Guillain-Barre Syndrome. Current treatments for CIDP have non-specific mechanisms of action and are ineffective in one-third of patients. Understanding the immune tolerance defects that result in PNS autoimmunity is critical for developing more effective, mechanism-based therapies. CIDP has recently been reported in rare patients with mutations in the Autoimmune Regulator (AIRE) gene. In parallel, we reported that mice with a dominant Aire G228W patient mutation on the autoimmune-prone NOD background (NOD.AireGW/+ mice) spontaneously develop autoimmune peripheral neuropathy that shares multiple features with sporadic CIDP. Together, these findings suggest that Aire plays an important role in preventing PNS autoimmunity in both mice and humans. Aire is a putative thymic transcription factor which promotes immune tolerance by upregulating thymic self-antigen expression and negative selection of self- reactive T cells, enhancing regulatory T cell development, and preventing B cell activation and autoantibody production. We hypothesize that these immunoregulatory mechanisms affected by Aire are also those important in maintaining immune tolerance towards the PNS. The NOD.AireGW/+ mouse therefore represents a valuable model for determining the immune tolerance defects underlying PNS autoimmunity. To this end, we propose to utilize our Aire-deficient model to: 1) identify the primary inciting PNS autoantigen(s) expressed in the thymus, 2) determine how Aire-deficiency alters the development of regulatory T cells important in suppressing PNS autoimmunity, and 3) determine the role of autoantibodies in Aire-mediated PNS autoimmunity. Because Aire affects tolerance mechanisms that are also disrupted in common autoimmune diseases, findings from this study will be applicable not only to the minority of patients with Aire mutations and CIDP, but also to sporadic CIDP patients who do not have Aire mutations. Additionally, findings from these studies will contribute to a broader understanding of how Aire functions to prevent autoimmunity.